1. Field of the Invention
The present invention is concerned with a novel improved method of preparing 5-(halophenyl)salicylic acid compounds in which a halobenzene compound is oxidatively coupled to an alkyl ester of salicylic acid, followed by hydrolysis of the ester.
More particularly, the present invention is concerned with preparation of 5-(2,4-difluorophenyl)salicylic acid, an important anti-inflammatory and analgesic therapeutic agent.
2. Brief Description of the Prior Art
The early use of palladium chloride catalysts in the oxidation of olefins led Van Helden et al. to a method for the oxidative coupling of aromatic compounds with palladium salts. See Smidt, Chem. and Ind., Jan. 13, 1962, pp. 54-61; and Van Helden and Verberg, Recueil, 84, pp. 1263-1273 (1965). Various modifications of this oxidative coupling method and related coupling methods have been put forward. See Stephenson et al., J. Chem. Soc., pp. 3632-3640 (1965); Davidson and Triggs, J. Chem. Soc., pp. 1331-1334 (1968); Iataaki and Yoshimoto, J. Org. Chem., Vol. 38, No. 1, pp. 76-79 (1973); Fujiuara et al., Bull. Chem. Soc. Jap., Vol. 43, No. 3, pp. 863-867 (1970); Arzoumanidis and Rauch, Chemtech, November 1973, pp. 700-702; and Rudenkov et al., Kinetika i Kataliz, Vol. 18, No. 4, pp. 915-920 (1977).
However, the methods of the prior art, when applied to the preparation of 5-(halophenyl) salicyclic acid compounds, have been found to be not only stoichiometric, i.e., not catalytic, but unselective as well, i.e., yielding the desired product in small proportions compared to other, undesired products. Thus, the methods of the prior art have been found unacceptable. The inherent problem to be overcome in the preparation of 5-(halophenyl)salicylic acid compounds by direct coupling of a halobenzene compound and an alkyl ester of salicylic acid, for example, methyl salicylate, lies in the very low reactivity of the halobenzene compound compared to the very high reactivity of the alkyl ester of salicylic acid. Thus, the predominant product of the coupling reaction is, for example, bis (methyl salicylate).
Contrary to what would be expected from the coupling methods of the prior art, the novel coupling method of the present invention provides not only a greatly improved product selectivity, but an exceptionally high catalyst turnover as well, thus affording a substantially improved method of preparing 5-(halophenyl)salicylic acid compounds.